tbuckley/cabot-search huggingface dataset:
Abstract C073: CRO-67 is a novel therapeutic for pancreatic cancer: Implications for tumor and stromal reprogramming
Authors: John Kokkinos, George Sharbeen, Koroush S. Haghighi, Janet Youkhana, Aparna Raina, Omali Pitiyarachchi, Quach Truong, Daniel Wenholz, Olivier Laczka, Naresh Kumar, David Goldstein, Phoebe A. Phillips
Journal: Cancer Research (2022)

Abstract Background: Pancreatic ductal adenocarcinoma (PDAC) is one of the most lethal malignancies and new therapeutic strategies are urgently required. A key drug delivery barrier and promoter of tumor progression is the fibrotic and heterogeneous microenvironment of PDAC which is mainly orchestrated by stromal cancer-associated fibroblasts (CAFs). Thus, any novel therapeutic strategy should not only target PDAC cells but should also aim to inhibit the pro-tumor properties of the PDAC stroma. However, to accurately evaluate the clinical potential of novel PDAC therapeutics, preclinical models are required that closely mimic the heterogeneity and multicellular architecture of human disease. Aim: We aimed to investigate the therapeutic potential of novel functionalized benzopyrans (CRO-05 &amp; CRO-67) in a patient-derived PDAC tumor explant model. Methods: We collected PDAC tumor samples from patients undergoing resection of their primary tumor. We cultured whole tumor explants (1-2mm diameter) on gelatin sponges. This model accurately maintains the multicellular tumor and stromal architecture of human PDAC [Kokkinos et al, Scientific Reports, 11,1941 (2021)]. Tumor explants were treated every 3 days with the racemic compound CRO-05 or its active enantiomer CRO-67 and explants were fixed in paraformaldehyde at day-12. Therapeutic response was assessed by immunohistochemistry for markers of tumor cells (cytokeratin), CAFs (α-Smooth Muscle Actin), cell-proliferation (Bromodeoxyuridine), and cell-death (TUNEL). Results: Treatment of human PDAC explants with CRO-05 resulted in reduced tumor cell frequency in 3/4 patients and in 4/4 patients, reduced CAF frequency, decreased cell-proliferation, and increased cell-death relative to controls. CRO-67 treatment in explants from 4/5 patients led to reduced tumor cell frequency, and in 5/5 patients, reduced CAF frequency, decreased cell-proliferation, and increased cell-death relative to controls. Conclusions: This work identifies the functionalized benzopyrans CRO-05 and CRO-67 as novel dual-cell therapeutics that potently inhibit both PDAC tumor cells and their surrounding CAFs and provides support for their clinical development as novel PDAC therapeutics. Citation Format: John Kokkinos, George Sharbeen, Koroush S. Haghighi, Janet Youkhana, Aparna Raina, Omali Pitiyarachchi, Quach Truong, Daniel Wenholz, Olivier Laczka, Naresh Kumar, David Goldstein, Phoebe A. Phillips. CRO-67 is a novel therapeutic for pancreatic cancer: Implications for tumor and stromal reprogramming [abstract]. In: Proceedings of the AACR Special Conference on Pancreatic Cancer; 2022 Sep 13-16; Boston, MA. Philadelphia (PA): AACR; Cancer Res 2022;82(22 Suppl):Abstract nr C073.
Abstract C076: Bacterial dysbiosis and its association with pancreatic cancer progression and poor survival
Authors: Holly B. Attebury
Journal: Cancer Research (2022)

Abstract Bacterial dysbiosis is emerging as an accomplice to carcinogenesis and is associated with pancreatic cancer progression and poorer survival. We found that gut bacteria can directly access the pancreas, and pancreatic tumors harbor a unique microbiome that differs from that of the healthy pancreas. We have also found that the tumor-associated microbiome regulates pancreatic cancer progression by skewing tumor-infiltrating immune cells towards an immunosuppressive phenotype. However, the exact mechanisms via which bacteria regulate immune cell function is still unknown. Inflammatory signaling by cancer cells and stromal cells in the tumor microenvironment has been shown to effectively regulate immune cell infiltration and differentiation. Our data suggests that pathogenic bacteria in the pancreatic tumor microenvironment can directly engage with pancreatic epithelial cells inducing proliferation and an inflammatory response. Specifically, the dominant Proteobacteria in the pancreatic tumor microenvironment induces the production of many pro-tumorigenic cytokines, such as IL-8 and IL-6, from cancer cells and pancreatic epithelial cells. Furthermore, we have found that pancreatic tumor- associated bacteria skews fibroblast differentiation towards an inflammatory, tumor-promoting phenotype. These findings show that pathogenetic tumor-associated bacteria can modulate the epithelial and stromal compartments in the pancreatic tumor microenvironment, thereby serving as mediators of tumorigenesis. Our results delineate the mechanisms via which microbes interface with the non-immune cell compartment in the tumor microenvironment and provide insight into therapeutic strategies for gut microbial modulation in treating pancreatic cancer. Citation Format: Holly B. Attebury. Bacterial dysbiosis and its association with pancreatic cancer progression and poor survival [abstract]. In: Proceedings of the AACR Special Conference on Pancreatic Cancer; 2022 Sep 13-16; Boston, MA. Philadelphia (PA): AACR; Cancer Res 2022;82(22 Suppl):Abstract nr C076.
Metformin can mitigate skeletal dysplasia caused by Pck2 deficiency
Authors: Zheng Li, Muxin Yue, Boon Chin Heng, Yunsong Liu, Ping Zhang, Yongsheng Zhou
Journal: International Journal of Oral Science (2022)

Abstract As an important enzyme for gluconeogenesis, mitochondrial phosphoenolpyruvate carboxykinase (PCK2) has further complex functions beyond regulation of glucose metabolism. Here, we report that conditional knockout of Pck2 in osteoblasts results in a pathological phenotype manifested as craniofacial malformation, long bone loss, and marrow adipocyte accumulation. Ablation of Pck2 alters the metabolic pathways of developing bone, particularly fatty acid metabolism. However, metformin treatment can mitigate skeletal dysplasia of embryonic and postnatal heterozygous knockout mice, at least partly via the AMPK signaling pathway. Collectively, these data illustrate that PCK2 is pivotal for bone development and metabolic homeostasis, and suggest that regulation of metformin-mediated signaling could provide a novel and practical strategy for treating metabolic skeletal dysfunction.
Abstract B015: Systemic reprogramming of fibroblasts and immune cells precedes metastatic spread in pancreatic cancer
Authors: Emily L. Lasse Opsahl, Ashley Velez-Delgado, Katelyn L. Donahue, Padma Kadiyala, Carlos Espinoza, Yaqing Zhang, Marina Pasca di Magliano
Journal: Cancer Research (2022)

Abstract Oncogenic KRAS (Kras*) is a near-universal driver of pancreatic ductal adenocarcinoma (PDA), and its activity is required for the formation of the PDA precursor lesions, pancreatic intraepithelial neoplasia (PanIN). PanIN formation is accompanied by fibrosis and immune cell infiltration, creating a precursor tumor microenvironment (PME) that is maintained and evolves through the disease progression. In mice bearing overt pancreatic cancer, pancreatic cells secrete specific factors to prime the liver and lung, forming the premetastatic niche. Presently, it remains to be elucidated at what stage of PDA tumorigenesis the premetastatic niche is initiated, as well as the mechanisms underlying this formation. As PDA patients are commonly diagnosed with metastatic disease, it is imperative to understand the mechanism underlying formation of the premetastatic niche, as well as determinants of metastasis outgrowth. To determine whether Kras*-dependent signals are required for the formation of the premetastatic niche, we used an inducible and reversible murine model of pancreas-specific Kras* expression developed by our group known as the iKras* mouse. We expressed Kras* in the pancreatic epithelium of adult mice for 16 weeks and validated the presence of advanced PanIN lesions without overt malignancy. We then performed single cell RNA sequencing (scRNA-seq) on the pancreas, liver, and lung of these mice, with liver and lung being common sites of metastasis for pancreatic cancer. We have previously shown that pancreatic fibroblasts are reprogrammed early during carcinogenesis, a finding that holds true at this later timepoint. Interestingly, we observed parallel changes in gene expression in fibroblasts, macrophages, and T cells in the lungs of PanIN bearing mice. Ongoing studies aim to validate the changes seen in the scRNA-seq and functionally evaluate systemic activation of fibroblasts and immune cells within the premetastatic niche. Citation Format: Emily L. Lasse Opsahl, Ashley Velez-Delgado, Katelyn L. Donahue, Padma Kadiyala, Carlos Espinoza, Yaqing Zhang, Marina Pasca di Magliano. Systemic reprogramming of fibroblasts and immune cells precedes metastatic spread in pancreatic cancer [abstract]. In: Proceedings of the AACR Special Conference on Pancreatic Cancer; 2022 Sep 13-16; Boston, MA. Philadelphia (PA): AACR; Cancer Res 2022;82(22 Suppl):Abstract nr B015.
Abstract IA007: Does cancer cell state matter? Moving from DNA genotype to RNA phenotype-directed therapies in cancer
Authors: Alex K. Shalek
Journal: Cancer Research (2022)

Abstract Recent advances in high throughput genomic sequencing technologies have led to a detailed understanding of the genetic alterations that underlie human tumors. However, evidence increasingly indicates that using mutations alone to assign therapies has its limitations, even for cancers with actionable mutational heterogeneity. The advent of single-cell genomic technologies has confirmed extensive mutational heterogeneity in human tumors but also revealed that the complexity of cancer extends to variation in cell transcriptional state. Deciphering whether transcriptional variation informs treatment response heterogeneity represents a new but poorly understood frontier in cancer therapeutics. In pancreatic ductal adenocarcinoma (PDAC), clinically relevant RNA expression states exist but our understanding of their drivers, stability, and relationship to therapeutic response is limited. To examine these attributes systematically, we profiled metastatic biopsies and matched organoid models at single-cell resolution. We identify a new intermediate PDAC transcriptional cell state and uncover distinct site- and state-specific tumor microenvironments. Moreover, we reveal strong organoid culture-specific biases in cancer cell transcriptional state representation and nominate critical factors missing from the ex vivo microenvironment. By adding back specific factors, we restore in vivo expression state heterogeneity and show plasticity in culture models, demonstrating that microenvironmental signals are critical regulators of cell state. Importantly, we prove that non-genetic modulation of cell state can significantly influence drug responses and uncover state-specific vulnerabilities. Our work provides a broadly applicable framework for mapping cell states across in vivo and ex vivo settings, identifying drivers of transcriptional plasticity, and manipulating cell state to target its associated vulnerabilities. Citation Format: Alex K. Shalek. Does cancer cell state matter? Moving from DNA genotype to RNA phenotype-directed therapies in cancer [abstract]. In: Proceedings of the AACR Special Conference on Pancreatic Cancer; 2022 Sep 13-16; Boston, MA. Philadelphia (PA): AACR; Cancer Res 2022;82(22 Suppl):Abstract nr IA007.
Abstract C058: Remodeling the tumor microenvironment by targeting integrin alpha V beta 3 (αvβ3) expressing cells in pancreatic cancer
Authors: Mayrel Palestino Dominguez, Philip Homan, Xianyu Zhang, Sandra Navas Reyes, Theresa Guerin, Laura Bassel, Zhi-ren Liu, Serguei Kozlov, Christine Alewine
Journal: Cancer Research (2022)

Abstract ProAgio is a therapeutic cytotoxin that targets and kills integrin αvβ3-expressing cells, resulting in reduced tumor collagen, decreased formation of new blood vessels in the tumor microenvironment (TME), and prolonged survival in mouse models of pancreatic ductal adenocarcinoma (PDAC). ProAgio is currently being tested in a Phase 1 dose-finding study in patients with solid tumors including pancreas cancers. The cell subsets within the PDAC TME that express integrin αvβ3 and could be subject to ProAgio-mediated killing have not been previously studied. Using the KPC genetically engineered mouse model of PDAC, we found that ProAgio (20 mg/kg daily, x7 days) restrained tumor growth by 20% compared to vehicle treatment without changing the cancer cell proliferation rate. We subsequently re-analyzed publicly available scRNA-seq PDAC datasets to identify cells present in human and mouse PDAC tumors that co-express integrins αv and β3 and could be targets of ProAgio. We found that specific subsets of cancer-associated fibroblasts (CAFs), monocytes and macrophages expressed both integrins. Flow cytometry was performed on cells dissociated from orthotopically implanted KPC-derived tumors treated for 15 days with ProAgio or vehicle to identify TME subsets affected by ProAgio treatment. There was no significant difference in the myofibroblast (myCAF) subset, but an increase in the percentage of inflammatory CAFs (iCAFs) was seen. ProAgio treatment also significantly increased the percentage of conventional dendritic cells which play a pivotal role in antigen recognition and T cell priming. T cell abundance was unchanged, but a decrease in B cells was observed. These data demonstrate that ProAgio treatment modifies specific immune and fibroblast subsets within the PDAC TME. Ongoing studies seek to further delineate the cell subtypes affected by ProAgio and the cytokine and chemokine mediators responsible for these changes. Citation Format: Mayrel Palestino Dominguez, Philip Homan, Xianyu Zhang, Sandra Navas Reyes, Theresa Guerin, Laura Bassel, Zhi-ren Liu, Serguei Kozlov, Christine Alewine. Remodeling the tumor microenvironment by targeting integrin alpha V beta 3 (αvβ3) expressing cells in pancreatic cancer [abstract]. In: Proceedings of the AACR Special Conference on Pancreatic Cancer; 2022 Sep 13-16; Boston, MA. Philadelphia (PA): AACR; Cancer Res 2022;82(22 Suppl):Abstract nr C058.
Abstract C035: Biotherapeutic strategies targeting the CXCR2 axis for depletion of myeloid-derived suppressor cells in pancreatic ductal adenocarcinoma
Authors: Ben N. Christopher, Reeder Robinson, Leticia Reyes, Lena Golick, Ashton Basar, Nathan Dolloff
Journal: Cancer Research (2022)

Abstract Pancreatic Ductal Adenocarcinoma (PDAC) has a 5-year survival rate of only 10%, and limited treatment options exist. Immune checkpoint inhibitors are effective in a variety of cancer types; however, the complex immunosuppressive tumor microenvironment (TME) of PDAC is a significant barrier to immunotherapy. Myeloid-derived suppressor cells (MDSCs) are abundant in PDAC tumors from humans and mouse models. MDSCs suppress effector T cell function, leading us to hypothesize that targeting tumor MDSCs would be an effective therapeutic strategy for PDAC and enhance the efficacy of T cell-based immunotherapy. Our preliminary data and the work from others shows that CXCR2 ligands such as CXCL8/IL-8, CXCL5/ENA78, and CXCL1/GROα are the most abundant soluble factors secreted by PDAC cells. CXCR2 ligands are critical for the homing of myeloid cells to sites of injury in cutaneous wound healing, suggesting that dysregulated secretion of CXCR2 chemokines in PDAC may mimic a wound healing response that attracts myeloid cells and promotes the expansion of MDSCs and an immunosuppressive TME. To test this hypothesis, we have designed multiple biotherapeutic molecules that exploit CXCL5/ENA78 and CXCL1/GROa to target and eliminate MDSCs from PDAC tumors. Specifically, we have generated Pseudomonas aeruginosa exotoxin (ExoA) and IgG-Fc fusion proteins that will be used to deliver cytotoxic payloads to MDSCs. A variety of CXCR2 knockout and knock-in models will be used to demonstrate CXCR2 dependence and elimination of MDSCs in vitro. In vivo, we are utilizing the KPC (LSL-KrasG12D/+;LSL-Trp53R172H/+;Pdx-1-Cre) mouse model of PDAC, which we've shown in preliminary studies to, like human PDAC, support an abundance of MDSCs in tumors as well as secondary lymphoid organs such as the spleen. We anticipate that this study will demonstrate the therapeutic potential and actionability of targeting MDSCs and will provide novel biotherapeutic drug candidates that will ultimately improve immunotherapy outcomes in patients with PDAC. Citation Format: Ben N. Christopher, Reeder Robinson, Leticia Reyes, Lena Golick, Ashton Basar, Nathan Dolloff. Biotherapeutic strategies targeting the CXCR2 axis for depletion of myeloid-derived suppressor cells in pancreatic ductal adenocarcinoma [abstract]. In: Proceedings of the AACR Special Conference on Pancreatic Cancer; 2022 Sep 13-16; Boston, MA. Philadelphia (PA): AACR; Cancer Res 2022;82(22 Suppl):Abstract nr C035.
Abstract IA005: Generating T cell responses against pancreatic cancer
Authors: Katelyn T. Byrne
Journal: Cancer Research (2022)

Abstract The ultimate promise of tumor immunotherapy is dependent on the generation of an effective immune response against cancer, including CD4 and CD8 T cells. However, driving T cell responses in tumors such as pancreatic ductal adenocarcinoma (PDAC) requires overcoming significant hurdles in the tumor microenvironment (TME). Local and systemic suppression of dendritic cell function depresses endogenous T cell immunity against PDAC, which is further exacerbated by tumor cell intrinsic recruitment of suppressive myeloid cells and macrophages to the tumor site. To bypass these barriers, we’ve utilized agonistic anti-CD40 antibody, which mimics the endogenous CD40 ligand, to license and mature dendritic cells and re-educate tumor-associated myeloid cells towards a Th1/M1 phenotype in the PDAC TME. Using the KrasLSL-G12D/+,Trp53LSL-R172H/+,Pdx1-Cre (KPC) genetically engineered mouse model of pancreatic cancer, we show that combining standard-of-care chemotherapy with CD40 agonism promotes clonal T cell activation and expansion locally in the tumor site, resulting in regressions and cures of established tumors. This CD40-induced T cell response was further enhanced by the addition of dual immune checkpoint blockade (anti-PD-1 and anti-CTLA-4), but was independent of classical innate immune sensors such as Type I interferon receptor (IFNAR) and toll-like receptors (TLRs) previously thought to be critical for the generation of T cell immunity against tumors. These studies formed the preclinical rationale for trials investigating the use of agonistic CD40 therapy for patients with resectable or metastatic PDAC, and provided insight for immunological correlates of response in the clinical setting. More recently, we have reported on the negative impact of chemotherapy on the developing anti-tumor T cell response, emphasizing the need for additional investigations into the combination and sequencing of treatment modalities for enhanced outcomes in patients with PDAC. These studies reveal the potency of using an immunologically relevant mouse model to interrogate immune interventions in PDAC for patients with the greatest unmet clinical need. Citation Format: Katelyn T. Byrne. Generating T cell responses against pancreatic cancer [abstract]. In: Proceedings of the AACR Special Conference on Pancreatic Cancer; 2022 Sep 13-16; Boston, MA. Philadelphia (PA): AACR; Cancer Res 2022;82(22 Suppl):Abstract nr IA005.
Abstract B063: Differential pathway engagement and the biological consequences of KRAS variants in cancer
Authors: Yanixa Quiñones Avilés, Jaffarguriqbal Singh, Wenxue Li, Yong Kong, Yansheng Liu, Mandar Deepak Muzumdar
Journal: Cancer Research (2022)

Abstract KRAS is a proto-oncogene found mutated in &amp;gt;90% of pancreatic ductal adenocarcinomas (PDAC) and encodes for a GTPase that mediates signaling transduction through the mitogen-activated protein kinase (MAPK) and PI3K/AKT pathways. Mutations in amino acids G12, G13, and Q61 prevent its inactivation by regulatory GTPase-activating proteins (GAPs), resulting in its constitutive activation. Previous work indicates that KRAS mutants possess unique biochemical differences that could result in divergent allele-specific signaling networks, underscoring unique vulnerabilities and response to treatment. Furthermore, preclinical and clinical data reveal allele-specific differences in tumor initiation capacity and patient prognosis in PDAC. Therefore, dissecting the biochemical and biological differences among KRAS variants would allow the identification of new allele-specific strategies for therapy. We hypothesize that the biochemical differences between KRAS variants result in differential signaling pathway engagement, affecting cellular behavior and tumorigenic properties. To study the biology of KRAS mutant variants in PDAC, we used CRISPR-Cas9 to generate KRAS-deficient PDAC cell lines which survived KRAS ablation through adaptive and reversible signaling rewiring. Our initial observations suggested that, at comparable expression levels, KRAS mutants diverge in their baseline signaling through the canonical MAPK and PI3K pathways. Therefore, we leveraged this unique isogenic system to uncover allele-specific differences between KRAS variants in global gene expression (by RNA-seq) and phosphoproteomic signaling networks (by data-independent acquisition mass spectroscopy; DIA-MS). We further employed a multiplexed competitive fitness approach using a sequence-based readout to assess changes in cellular fitness in response to drug perturbations (KRASi, PI3Ki, SHP2i, ERKi, RTKi and MEKi). Our findings suggest that KRAS mutants cluster into groups that diverge in downstream pathway engagement and gene expression, leading to cluster-specific differences in drug sensitivity. Our findings suggest that elucidating the signaling differences between KRAS alleles and their biological functions could translate to novel therapeutic strategies in PDAC and other KRAS mutant cancers. Citation Format: Yanixa Quiñones Avilés, Jaffarguriqbal Singh, Wenxue Li, Yong Kong, Yansheng Liu, Mandar Deepak Muzumdar. Differential pathway engagement and the biological consequences of KRAS variants in cancer [abstract]. In: Proceedings of the AACR Special Conference on Pancreatic Cancer; 2022 Sep 13-16; Boston, MA. Philadelphia (PA): AACR; Cancer Res 2022;82(22 Suppl):Abstract nr B063.